The long-term goal of this research program is to elucidate the biochemical, physiological and behavioral correlates of voluntary alcohol consumption through study in animal models. The work will employ primarily 2 selectively bred lines of rats, one of which is for alcohol preference (the P line) and the other is for alcohol nonpreference or aversion (the NP line). Past work has shown that the P line exhibits many of the perceived requirements for an animal model of alcoholism, e.g. working to obtain ethanol voluntary consumption to pharmacologically significant levels of blood alcohol and development of physical dependence with chronic voluntary intake. The aims of the proposed granting period are to continue studies establishing the P rats as a animal model of alcoholism and to test the following hypotheses: 1) voluntary alcohol drinking behavior is genetically related, as result of the pleiotropic action of common genes, to certain CNS effects of ethanol, e.g. stimulation by low dose ethanol and tolerance to the depressant action of high dose ethanol, 2) tolerance develops to the CNS depressant but not to the stimulatory action of ethanol. It is postulated that this combination of responses promotes alcohol preference and sustained intake. Ongoing studies indicate that P rats exhibit stimulation with low dose ethanol whereas NP rats do not and that P rats develop tolerance to the depressant actions of ethanol more rapidly than do NP rats. The proposed studies will compare P with NP animals with respect to alcohol seeking behavior when alcohol is self-administered nonorally by the intragastric route, the development of functional tolerance to the low dose stimulatory and high dose depressant actions of ethanol, the development of metabolic tolerance, the effect of tolerance on ethanol self-administration, and the neurochemical effects of low and high dose ethanol in naive and tolerant animals. Genetic studies to determine the genotypic variance and covariance of alcohol preference and the other alcohol-related traits of interest will be performed in the offspring of P X NP crosses and in the recently constituted NIH (heterogeneous stock) rat. Finally, selection for alcohol preference and nonpreference will be initiated from the NIH heterogeneous stock rats and the covariance of the other alcohol-related traits of interest will be assessed.